Contact lens having a pharmaceutical agent releasably disposed therein

ABSTRACT

A contact lens having a pharmaceutical agent releasably disposed therein. The lens itself comprises a polymer of an unsaturated carboxylic acid ester of salicylic acid, the unsaturated carboxylic acid having up to 24 carbon atoms and 1-4 ethylenic double bonds, or a pharmaceutically acceptable salt of the salicylic acid ester.

RELATED APPLICATIONS

This is a divisional of U.S. application Ser. No. 08/970,583, filed Nov.14, 1997, U.S. Pat. No. 6,037,338, which is a divisional of U.S.application Ser. No. 08/785,979, filed Jan. 21, 1997, now U.S. Pat. No.5,910,511 issued Jun. 8, 1999, which is a divisional of U.S. applicationSer. No. 08/224,718, filed Apr. 8, 1994, now U.S. Pat. No. 5,760,261issued Jun. 2, 1998, which is a continuation-in-part of U.S. applicationSer. No. 07/853,428, filed Mar. 18, 1992, now U.S. Pat. No. 5,346,929issued Sep. 13, 1994, which is a divisional of U.S. application Ser.07/486,217, filed Feb. 28, 1990, now U.S. Pat. No. 5,120,089 issued Jun.9, 1992, the entire disclosures of which are hereby incorporated byreference and relied upon.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a method of treating anaspirin-treatable condition. The present invention further relates to acompound and a pharmaceutical composition for use in treating anaspirin-treatable -condition.

2. Background Information

Aspirin (acetylsalicylic acid), one of the oldest over-the-counter drugshaving been marketed since 1899, continues to be used for relief fromheadaches, fevers and arthritis pain. Aspirin works as an analgesic toreduce pain, an anti-pyretic to reduce fever and an anti-inflammatoryagent. Recently, aspirin has been shown to aid in the prevention ofheart attacks. However, aspirin does have undesirable side effects. Useof aspirin has been linked to Reye's Syndrome in children, hearingimpairment in heavy users, stomach problems, excessive bleeding andcertain rare but serious complications of pregnancy.

Other anti-inflammatory drugs that reduce pain such as acetaminophen(Tylenol) and ibuprofen (Motrin, Advil and Nuprin) are also available.However, these also are associated with potentially harmful sideeffects. Acetaminophen, the most preferred analgesic after aspirin, cancause delayed liver damage when used excessively and major kidney damagewith long-term chronic use.

SUMMARY OF THE INVENTION

Accordingly, it is an object of the present invention to provide analternative to aspirin which has lesser undesirable side effectsassociated with aspirin.

Further objects and advantages of the present invention will be clear toone skilled in the art from the description that follows.

In one embodiment, the present invention relates to a method of treatingan aspirin-treatable condition other than gout by administering to amammal in need of such treatment an amount sufficient to effect saidtreatment of a compound of Formula I

wherein R is an alkyl group (straight chain or branched chain) of atleast two carbon atoms, an alkenyl group, (straight chain or branchedchain), an aryl group; and X is hydrogen or a pharmaceuticallyacceptable salt thereof, e.g., where X is a non-toxic metal or ammonium.

Aspirin-treatable conditions include, but are not limited to, pain suchas headache and arthritis pain, fever, pre-eclampsia, and especiallyheart attacks and predisposition of heart attack.

In another embodiment, the present invention relates to a compound ofFormula I wherein R is an alkyl group (straight chain or branched chain)of at least 6 carbon atoms, an alkenyl group (straight chain or branchedchain) of 2 to 17 carbon atoms, an aryl group; or a pharmaceuticallyacceptable salt thereof.

In another embodiment, the present invention relates to a compound ofFormula I wherein R is an alkyl group (straight chain or branched chain)of at least 6 carbon atoms, an alkenyl group (straight chain or branchedchain) of 2 to 23 carbon atoms, an aryl group; or a pharmaceuticallyacceptable salt thereof.

In a further embodiment, the present invention relates to apharmaceutical composition for use in treating an aspirin-treatablecondition comprising a compound of Formula I wherein R is an alkyl group(straight chain or branched chain) of at least 2 carbon atoms, analkenyl group (straight chain or branched chain) of 2 to 17 carbonatoms, an aryl group, or a pharmaceutically acceptable salt thereof, inan amount sufficient to effect treatment of said condition, togetherwith a pharmaceutically acceptable carrier.

In a further embodiment, the present invention relates to apharmaceutical composition for use in treating an aspirin-treatablecondition comprising a compound of Formula I wherein R is an alkyl group(straight chain or branched chain) of at least 5, e.g., 6 to 23 or 17 to23, carbon atoms, an alkenyl group (straight chain or branched chain) of2 to 23 carbon atoms, an aryl group, or a pharmaceutically acceptablesalt thereof, in an amount sufficient to effect treatment of saidcondition, together with a pharmaceutically acceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the use of compounds of the followingFormula I

wherein R is an alkyl group (straight chain or branched chain) of 2 ormore carbon atoms (advantageously, 2 to 17 carbon atoms) or an alkenylgroup (straight chain or branched chain) of 2 to 23 carbon atoms, anaryl group (advantageously, phenyl), and X is hydrogen or apharmaceutically acceptable salt forming metal or group (advantageously,sodium, potassium, lithium, calcium or ammonium salts). Of the compoundsof Formula I, those in which R is unsaturated and those were R issaturated and contain more than 5 carbon atoms are believed to bedisclosed for the first time herein. The compounds are solid whitepowders.

Compounds of Formula I to which the invention relates include, but arenot limited to, propionylsalicylic acid and its sodium, potassium,lithium, ammonium and calcium salts; butyroylsalicyclic acid and itssodium, potassium, lithium, ammonium and calcium salts;valeroylsalicylic acid and its sodium, potassium and calcium salts;isovaleroyl-salicylic acid and its sodium, potassium, lithium, ammoniumand calcium salts; caproyl salicylic acid and its sodium, potassium,lithium and calcium salts; heptanoyl salicylic acid and its sodium,potassium, lithium, calcium and ammonium salts; stearoyl-salicylic acidand its sodium, potassium, lithium and calcium salts;methacryloyl-salicylic acid and its sodium, potassium, lithium andcalcium salts; crotonoyl-salicylic acid and its sodium, potassium andcalcium salts; oleoylsalicylic acid and its sodium, potassium, lithiumand calcium salts; the ammonium salt of propionylsalicylic acid; and theammonium, sodium, calcium, potassium and lithium salts ofacryloylsalicylic acid, as well as acryloylsalicylic acid itself.

Compounds of Formula I to which the invention also relates include, butare not limited to, unsaturated acid derivatives where the acid can haveup to 24 carbon atoms, i.e., when R is alkenyl, it can be 2 to 23 carbonatoms. Illustrative examples of such salicylic acid esters include thosefrom erucic acid (cis-13-docosenoic acid, R is 21), selacholeic acid (a24 carbon atom cis alkenoic acid), palmitoleic acid (16 carbon atomunsaturated acid) and arachidonic acid (20 carbon atoms, R is 19 carbonatoms and having four double bonds).

Particularly preferred are erucocyl salicylic acid and its sodium,potassium, lithium, ammonium and calcium salts. As starting materialsthere can be used erucoyl chloride, bromide, iodide and anhydride. Theprimary source of erucic acid is rapeseed oil. About 50% of theglyceride esters in rapeseed oil are esters of erucic acid.

Compounds of Formula I to which the invention also relates include, butare not limited to, saturated acid derivatives where the acid can haveup to 24 carbon atoms, i.e, when R is alkenyl, it can be 2 to 23 carbonatoms. Illustrative examples of such salicylic acid esters include thosefrom arachidic acid, behenic acid and lignoceric acid.

The compounds of Formula I can be made in the same manner as aspirin, byconventional acylation procedures (other than the ketene procedure), forexample, for typical procedures see U.S. Pat. No. 644,077; Bonhofer,U.S. Pat. No. 656,435; Hiemenz, U.S. Pat. No. 1,122,201; Gerngross, U.S.Pat. No. 1,217,862; Gruttefien, U.S. Pat. No. 1,338,297; Edmunds, U.S.Pat. Nos. 3,373,187 and 3,235,583; Berendes, U.S. Pat. Nos. 1,020,121and 1,113,742; Richter, U.S. Pat. No. 1,058,904; Busch, U.S. Pat. Nos.1,129,953 and 1,225,407; Allwey, U.S. Pat. No. 1,431,863; Lawrence, U.S.Pat. No. 2,003,374; Rothlenz, U.S. Pat. No. 2,052,663; Summus, U.S. Pat.No. 1,689,696; Stoesser, U.S. Pat. No. 2,987,539; Adams, U.S. Pat. No.3,064,038; Schlosser, U.S. Pat. No. 3,109,019; Satzinger, U.S. Pat. No.4,724,266; and Coleman, U.S. Pat. No. 2,207,611.

Conventional acylation procedures include reacting salicylic acid withthe corresponding acyl halide, such as acyl chloride or thecorresponding acid anhydride. Typical reactants include, but are notlimited to, acryloyl chloride, methacryloyl chloride, propionylchloride, stearoyl chloride, oleoyl chloride, propionic anhydride,butyric anhydride, acrylic anhydride and methacrylic anhydride. Forexample, it is well known that a phenol can be reacted using theSchotton-Baumann method with acyl halide in the presence of aqueousalkali or in the presence of pyridine using the Einhorn procedure. Thus,salicylic acid can be reacted with propionyl chloride or acryloylchloride in the presence of aqueous sodium hydroxide or aqueouspotassium hydroxide in a standard Schotten-Baumann method reaction.

The compounds of Formula I can also be made by ester interchange. Forexample, methyl acrylate and/or methyl methacrylate can be reacted withsalicylic acid in the presence of a solvent such as benzene and apolymerization inhibitor. Appropriate catalysts for use in the presentinvention include, but are not limited to anhydrides, sodium acetate andsulfuric acid. Polymerization inhibitors, for use in the presentinvention, include, but are not limited to, 1,4-dihydroxybenzene,4-tert-butyl-1,2-hydroxybenzene, 4-methoxyphenol,2,4-dichloro-6-nitrophenol, 7-amino-1-hyroxynaphthalene, p-benzoquinone,2,6-dichloro-4-benzoquinone, 1-amino-4-hydroxyanthraquinone, 1-naphthylamine and divinylethyne.

As an alternative, methyl methacrylate (or methyl acrylate) can betransesterified with salicyclic acid in a solvent such as acetone,benzene or toluene in the presence of a polymerization inhibitor. Inaddition, the free acrylic acid or methacrylic acid can be reacted withsalicylic acid in the presence of a catalyst. A polymerization inhibitorcan be optionally added.

When R of Formula I is an aryl, such as phenyl, benzoylsalicylic acid orits sodium, potassium, calcium, lithium or ammonium salt can be formed.The synthesis procedure would be the same, that is, reacting salicylicacid with benzoyl chloride in the Schotten-Baumann method.

The compounds of Formula I can be used in treatment situations where theuse of aspirin is indicated, (see, for example, Washington Post, HealthSection, Jul. 25, 1989, pages 10-14).

The compounds of the present invention are for use in human medicine orveterinary medicine, such as in treating dogs, cats, horses and cattle.

The present invention also relates to pharmaceutical compositionscomprising as the active ingredient, at least one compound of Formula I.The composition can be present in dosage unit form, for example, as apill, capsule, tablet or gel tablet. The composition can furthercomprise other pharmacologically active materials, for example, aspirin,streptokinase, urokinase or tissue plasminogen activator (see Sarnoff,U.S. Pat. No. 4,661,469). The composition of the invention includes apharmaceutically acceptable carrier or diluent, (See for example, Engel,U.S. Pat. No. 4,463,995, col. 13, line 35 to col. 15, line 54).

The dosage of the compounds of the present invention can be readilydetermined by one skilled in the art and, for example, range from 1 to10 milligrams or even up to 1 gram. For example, in preventing heartattacks or as an analgesic there is used a dose of 325 milligrams ofpropionyl salicylic acid or acryloylsalicylic acid or 700 milligrams ofstearoylsalicylic acid or oleoylsalicylic acid is administered to anaverage adult male. For preventing pre-eclampsia, there is used 50milligrams of propionyl salicylic acid, acryloyl salicylic acid ormethacryloyl salicylic acid or 125 milligrams of stearoyl salicylic acidor oleoyl salicylic acid. For children, there is used 60 to 70milligrams of propionyl salicylic acid, acryloyl salicylic acid ormethacryloyl salicylic acid or 150 to 175 milligrams ofstearoylsalicylic acid or oleyl salicylic acid.

The dosage of the compound when given orally, such as in the form of apill, generally will be higher than when the compound is administeredintravenously.

The compounds of Formula I of the present invention are conventionallyemployed in pills or other solid formulation in an amount of about 0.5to 5 mg/kg or even about 7 mg/kg body weight or in the case of highermolecular weight compounds, such as lauroyl salicylic acid, stearoylsalicylic acid or oleoyl salicylic acid, in an amount up to about 10mg/kg of body weight.

As a first example, a capsule can be prepared by mixing about 500 gramsof a compound of the present invention with about 175 grams ofmicrocrystalline cellulose, about 315 grams of lactose and about 10grams of magnesium stearate. About 100 mg of the mixture is, in eachcase, filled into solid size 3 gelatin capsules. One capsule containsabout 40 mg of active material, such as propionyl salicylic acid oracryloyl salicylic acid.

As a second example, a tablet can be prepared comprising about 1 to 1000mg, usually about 10 to 500 mg, of active material together withmicrocrystalline cellulose, starch and magnesium stearate. A typicalformula for such a tablet follows:

microcrystalline cellulose 130 mg modified starch 20 mg stearate 5.5 mgpolyvinylpyrrolidone 22 mg stearic acid 30 mg propionyl salicylic acid300 mg

As a third example, a tablet can be formulated as follows: about 8 kg ofa compound of Formula I, such as propionyl salicylic acid or acryloylsalicylic acid, about 5 kg lactose and about 3 kg of microcrystallinecellulose are mixed with about 0.3 kg of polyvinyl pyrrolidone in about12 kg of water. There is added about 3.45 kg of microcrystallinecellulose, about 2 kg corn starch, about 0.05 kg highly dispersed silicaand about 0.2 kg magnesium stearate. The mixture is molded into a tabletweighing about 220 mg and having about a 9 mm diameter and a radius ofcurvature of about 13.5. Each tablet contains about 80 mg of activematerial.

In addition to the above-described use of the compounds of Formula I asan aspirin substitute, one skilled in the art will also appreciate thatthe compounds containing ethylenic double bonds can be polymerized usingmethods, cross-linking agents and free catalysts known in the art (see,for example, Guttag, U.S. Pat. No. 3,860,490, issued Jan. 14, 1975 andSteckler, U.S. Pat. No. 3,532,679, issued Oct. 6, 1970). For example,there can be employed azobisisobutyronitrile, e.g., in an amount of 0.05to 1%, specifically 0.5% bound on the monomer, or there can be used thesame amount of a peroxide, e.g., tert-butyl peroxide. Polymers thusformed can be used, for example, as an implant (the monomer leaching outinto its environment over time). Alternatively, the polymer can be usedwith or without monomer in the preparation of a container, for example,a molded cup or a cup with a layer of polymer/monomer being present onthe inner surface of the cup. In this embodiment, when the monomer ispresent it will leach out of the layer into the fluid contained withinthe cup. In addition, the polymer can be used in the construction of acontact lens using known methods (see, for example, Wichterle, U.S. Pat.No. 3,220,960, issued on Nov. 30, 1965). The lens can be constructed soas to include a compartment disposed within which is a pharmaceuticalagent, for example, a compound of Formula I, which agent is releasedfrom the lens into its environment and potentially into the blood streamof the user.

In molding a cup, a lens or an implant, for example, there can be formedcopolymers, e.g., a copolymer of methacryloyl salicylic acid (oracryloyl salicylic acid) with 0.02-10%, of a polyalkylene glycoldiacrylate or dimethacrylate, e.g., 2% of ethylene glycoldimethacrylate.

All patents and publications mentioned herein are hereby incorporated byreference.

While the foregoing invention has been described in some detail forpurposes of clarity and understanding, it will be clear to one skilledin the art from a reading of this disclosure that various changes inform and detail can be made without departing from the true scope of theinvention.

What is claimed is:
 1. A contact lens having a pharmaceutical agent releasably disposed therein wherein the lens itself comprises a polymer of an unsaturated carboxylic acid ester of salicylic acid, said unsaturated carboxylic acid having up to 24 carbon atoms and 1-4 ethylenic double bonds, or a pharmaceutically acceptable salt of said salicylic acid ester, and wherein the unsaturated carboxylic acid ester group is attached to the benzene ring of the salicylic acid through the phenolic oxygen atom.
 2. A contact lens according to claim 1 wherein the lens is made of a polymer comprising acryloyl salicylic acid or methacryloyl salicylic acid units or a pharmaceutically acceptable salt of said salicylic acid.
 3. A contact lens according to claim 1 wherein the unsaturated carboxylic acid contains 16 to 24 carbon atoms.
 4. A contact lens according to claim 3 wherein the unsaturated carboxylic acid is erucic acid.
 5. A contact lens according to claim 3 wherein the unsaturated carboxylic acid has 4 ethylenic double bonds.
 6. A contact lens according to claim 2 wherein the polymer comprises acryloyl salicylic acid units.
 7. A contact lens according to claim 2 wherein the polymer comprises methacryloyl salicylic acid units.
 8. A contact lens according to claim 1 wherein the unsaturated carboxylic acid contains 1 ethylenic double bond.
 9. A contact lens according to claim 8 wherein the unsaturated carboxylic acid contains 16 to 24 carbon atoms.
 10. A contact lens according to claim 9 wherein the polymer comprises olcoyl salicylic acid units.
 11. A contact lens according to claim 5 wherein the unsaturated carboxylic acid is arachidonic acid.
 12. A contact lens according to claim 9 wherein the unsaturated carboxylic acid is selacholeic acid.
 13. A contact lens according to claim 9 wherein the unsaturated carboxylic acid is palmitoleic acid.
 14. A contact lens according to claim 1 wherein the unsaturated carboxylic acid ester of salicylic acid has the formula:

wherein R is an alkenyl group of 2 to 17 carbon atoms and X is hydrogen or a pharmaceutically acceptable salt thereof. 